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Serum-free light chains adjusted for renal function are a potential biomarker for post-transplant lymphoproliferative disorders

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Abstract

Post-transplant lymphoproliferative disease (PTLD) is a serious complication of solid organ transplantation. As early diagnosis remains challenging, we investigated the utility of serum-free light chain (FLC) and heavy chain/light chain pairs (HLC) as diagnostic biomarkers. Pre-treatment serum FLC and HLC levels were measured in 20 patients at their first diagnosis of B cell PTLD and in 14/20 patients during follow-up. Results were compared to serum FLC/HLC levels of 90 matched PTLD-free transplanted controls. Renal dysfunction was common in both cohorts, and combined FLC levels were often elevated above the conventional upper limit of normal (45.7 mg/L). Combined FLC levels were higher in patients with PTLD than in transplant controls (p = 0.013), and levels above the conventional ULN were associated with PTLD (OR 3.2, p = 0.05). Following adjustment to cystatin C as a marker of renal function an even stronger association was found for a (dimensionless) threshold value of 37.8 (OR 8.9, p < 0.001). In addition, monoclonal proliferation (abnormal FLC ratio, using an established renal range cutoff) was more common in PTLD than in controls (3/20 vs. 2/90, p = 0.04). Following therapy, at the time of protocolised restaging, patients experiencing subsequent sustained complete remission displayed lower FLC levels than those not experiencing such remission (p = 0.053). No relationship with HLC results was seen. Elevated polyclonal FLC levels (especially when adjusted for renal function) and monoclonal proliferation are a potential biomarker for PTLD diagnosis and disease surveillance. However, prospective validation is necessary before FLC measurement should be incorporated in follow-up of transplant recipients and PTLD management.

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Abbreviations

CHOP:

Chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone

cFLC:

Combined free light chain

CR:

Complete remission

CRP:

C-reactive protein

DLCBL:

Diffuse large B cell lymphoma

EBV:

Epstein–Barr virus

ECOG :

Eastern Cooperative Oncology Group

FLC:

Free light chain

FLCadj :

Adjusted free light chain

HLC:

Serum heavy/light chain

MALT:

Mucosal-associated lymphoid tumour

OR:

Odds ratio

PTLD:

Post-transplant lymphoproliferative disorder

ROC:

Receiver operating characteristic

ULN:

Upper limit of normal

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Acknowledgments

We thank the Binding Site Ltd. for the provision of the assays for this study and for technical support, in particular, Dr. Anne Burmeister.

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Author notes

  1. RB and AS contributed equally to this work and should be considered as co-lead authors of this manuscript

Authors and Affiliations

  1. Department of Nephrology and Kidney Transplantation, Queen Elizabeth Hospital Birmingham, Birmingham, UK

    R. Borrows & P. Cockwell

  2. University of Birmingham, Birmingham, UK

    R. Borrows

  3. Department of Internal Medicine II: Hematology and Oncology, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany

    A. Scheer, H. Zimmermann & R. U. Trappe

  4. Department of General, Visceral-, Thoracic-, Transplantation- and Pediatric Surgery, University Medical Centre Schleswig-Holstein, Campus Kiel, Kiel, Germany

    F. Braun

  5. Department of Pathology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany

    I. Anagnostopoulos

  6. Department of Hematology and Oncology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany

    H. Riess & R. U. Trappe

  7. German PTLD Study Group, Department of Hematology and Oncology, DIAKO Ev. Diakonie-Krankenhaus gGmbH Bremen, Gröpelinger Heerstrasse 406-408, 28239, Bremen, Germany

    H. Zimmermann & R. U. Trappe

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Contributions

RB and RUT are the principal investigators, coordinated the research and take primary responsibility for the paper. HZ, HR and RUT recruited the patients and collected clinical data. FB, RB and PC recruited the controls. AS did the laboratory work. AS, RB, PC and RUT analysed and interpreted the data. IA served as reference pathologists. AS, RB, PC, HZ and RUT wrote the paper. All authors had full access to the final version of the manuscript and agreed to publication.

Corresponding author

Correspondence to R. U. Trappe.

Ethics declarations

Ethical approval for this study was provided by the local committees of both institutions. The study was conducted according to the guidelines of the Declaration of Helsinki.

Disclosures

The Binding Site provided FLC, HLC and cystatin C assays free of charge. The Binding Site played no role in the analysis of the clinical data, its interpretation or the manuscript preparation. The content of the manuscript remains the responsibility of the listed authors.

Conflicts of interest

The authors declare that they have no conflict of interest.

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Informed consent was obtained from all individual participants included in the study.

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Borrows, R., Scheer, A., Cockwell, P. et al. Serum-free light chains adjusted for renal function are a potential biomarker for post-transplant lymphoproliferative disorders. Ann Hematol 98, 625–632 (2019). https://doi.org/10.1007/s00277-018-03591-w

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  • DOI: https://doi.org/10.1007/s00277-018-03591-w

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